Found! Lost puzzle piece involved in gene regulation revealed in search that began in water-loving, one-celled organism

After an intrepid, decade-long search, Johns Hopkins Medicine scientists say they have found a new role for a pair of enzymes that regulate genome function and, when missing or mutated, are linked to diseases such as brain tumors, blood cancers and Kleefstra syndrome — a rare genetic, neurocognitive disorder.

The new findings, published Nov. 21 in Epigenetics & Chromatin, could eventually help scientists understand diseases caused by disruption of these enzymes and develop new treatments for them.

“Developing a better understanding of how enzymes impact the activity of our genomes offers valuable insights into biology and can help researchers design new therapeutic approaches for disease,” says Sean Taverna, Ph.D., associate professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine.

The search began more than a decade ago, when Taverna was looking for factors that influence DNA activity in Tetrahymena thermophila — a one-celled, fresh water dwelling organism. During the original study, the research team found a previously unknown signal that the single-celled creature uses to “mark” genes it has turned off.

The location of the mark is on histone proteins, which act as spools that tightly wind DNA, often turning off genes and protecting DNA from damage. If Tetrahymena are not able to add the marks — a process called methylation, which adds chemical tags to a part of histones called H3K23 — the DNA becomes damaged and the cells grow poorly.

In a follow up study published in 2016, Taverna found that the H3K23 location is conserved between Tetrahymena and mammals, including humans. However, the enzymes that control how the chemical tags are placed on H3K23 differ between the species.

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